scholarly journals Hypercapnia causes cellular oxidation and nitrosation in addition to acidosis: implications for CO2 chemoreceptor function and dysfunction

2010 ◽  
Vol 108 (6) ◽  
pp. 1786-1795 ◽  
Author(s):  
Jay B. Dean
Keyword(s):  
Redox Reactions ◽  
Nitrosative Stress ◽  
Carbonic Acid ◽  
Hydration Reaction ◽  
Hypercapnic Acidosis ◽  
Cellular Mechanisms ◽  
Target Membrane ◽  
Chemosensitive Areas ◽  
Cellular Oxidation ◽  
Solitary Complex

Cellular mechanisms of CO2 chemoreception are discussed and debated in terms of the stimuli produced during hypercapnic acidosis and their molecular targets: protons generated by the hydration of CO2 and dissociation of carbonic acid, which target membrane-bound proteins and lipids in brain stem neurons. The CO2 hydration reaction, however, is not the only reaction that CO2 undergoes that generates molecules capable of modifying proteins and lipids. Molecular CO2 also reacts with peroxynitrite (ONOO−), a reactive nitrogen species (RNS), which is produced from nitric oxide (•NO) and superoxide (•O2−). The CO2/ONOO− reaction, in turn, produces additional nitrosative and oxidative reactive intermediates. Furthermore, protons facilitate additional redox reactions that generate other reactive oxygen species (ROS). ROS/RNS generated by these redox reactions may act as additional stimuli of CO2 chemoreceptors since neurons in chemosensitive areas produce both •NO and •O2− and, therefore, ONOO−. Perturbing •NO, •O2−, and ONOO− activities in chemosensitive areas modulates cardiorespiration. Moreover, neurons in at least one chemosensitive area, the solitary complex, are stimulated by cellular oxidation. Together, these data raise the following two questions: 1) do pH and ROS/RNS work in tandem to stimulate CO2 chemoreceptors during hypercapnic acidosis; and 2) does nitrosative stress and oxidative stress contribute to CO2 chemoreceptor dysfunction? To begin considering these two issues and their implications for central chemoreception, this minireview has the following three goals: 1) summarize the nitrosative and oxidative reactions that occur during hypercapnic acidosis and isocapnic acidosis; 2) review the evidence that redox signaling occurs in chemosensitive areas; and 3) review the evidence that neurons in the solitary complex are stimulated by cellular oxidation.

Intracellular pH response to hypercapnia in neurons from chemosensitive areas of the medulla

1997 ◽  
Vol 273 (1) ◽  
pp. R433-R441 ◽  
Author(s):  
N. A. Ritucci ◽  
J. B. Dean ◽  
R. W. Putnam
Keyword(s):  
Intracellular Ph ◽  
Medulla Oblongata ◽  
Imaging System ◽  
Brain Slices ◽  
Ventrolateral Medulla ◽  
Disulfonic Acid ◽  
Hypoglossal Nucleus ◽  
Hypercapnic Acidosis ◽  
Sprague Dawley ◽  
Chemosensitive Areas

We investigated whether neurons in two chemosensitive areas of the medulla oblongata [nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM)] respond to hypercapnia differently than neurons in two nonchemosensitive areas of the medulla oblongata [inferior olive (IO) and hypoglossal nucleus (Hyp)]. Medullary brain slices from preweanling Sprague-Dawley rats were loaded with 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein, and intracellular pH (pHi) was followed in individual neurons at 37 degrees C with the use of a fluorescence imaging system. Most neurons from the NTS and VLM did not exhibit pHi recovery when CO2 was increased from 5 to 10% at constant extracellular HCO3- concentration [extracellular pH (pHo) decreased approximately 0.3 pH unit] (hypercapnic acidosis). However, when CO2 was increased from 5 to 10% at constant pHo (isohydric hypercapnia), pHi recovery was seen. In contrast, all neurons from the IO and Hyp exhibited pHi recovery during hypercapnic acidosis. All pHi recovery in the four areas studied was inhibited by 1 mM amiloride and unaffected by 0.5 mM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. These data indicate that 1) pHi regulation differs between neurons in chemosensitive (NTS and VLM) and nonchemosensitive (IO and Hyp) areas of the medulla, 2) pHi recovery is due solely to Na+/H+ exchange in all four areas, and 3) Na+/H+ exchange is more sensitive to inhibition by extracellular acidosis in NTS and VLM neurons than in IO and Hyp neurons.

scholarly journals Implications of Oxidative and Nitrosative Post-Translational Modifications in Therapeutic Strategies against Reperfusion Damage

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 749
Author(s):  
Mabel Buelna-Chontal ◽  
Wylly R. García-Niño ◽  
Alejandro Silva-Palacios ◽  
Cristina Enríquez-Cortina ◽  
Cecilia Zazueta
Keyword(s):  
Redox Reactions ◽  
Nitrosative Stress ◽  
Therapeutic Strategies ◽  
Oxygen Species ◽  
Post Translational Modifications ◽  
Pathological Conditions ◽  
Reperfusion Damage ◽  
Modified Proteins ◽  
Protective Signaling ◽  
The Impact

Post-translational modifications based on redox reactions “switch on-off” the biological activity of different downstream targets, modifying a myriad of processes and providing an efficient mechanism for signaling regulation in physiological and pathological conditions. Such modifications depend on the generation of redox components, such as reactive oxygen species and nitric oxide. Therefore, as the oxidative or nitrosative milieu prevailing in the reperfused heart is determinant for protective signaling, in this review we defined the impact of redox-based post-translational modifications resulting from either oxidative/nitrosative signaling or oxidative/nitrosative stress that occurs during reperfusion damage. The role that cardioprotective conditioning strategies have had to establish that such changes occur at different subcellular levels, particularly in mitochondria, is also presented. Another section is devoted to the possible mechanism of signal delivering of modified proteins. Finally, we discuss the possible efficacy of redox-based therapeutic strategies against reperfusion damage.

scholarly journals Normobaric hyperoxia stimulates superoxide and nitric oxide production in the caudal solitary complex of rat brain slices

2016 ◽  
Vol 311 (6) ◽  
pp. C1014-C1026 ◽  
Author(s):  
Geoffrey E. Ciarlone ◽  
Jay B. Dean
Keyword(s):  
Nitric Oxide ◽  
Brain Slice ◽  
Neuronal Excitability ◽  
Nitrosative Stress ◽  
Brain Slices ◽  
Normobaric Hyperoxia ◽  
Fluorogenic Dyes ◽  
Cellular Excitability ◽  
Cellular Dysfunction ◽  
Solitary Complex

Central CO2-chemosensitive neurons in the caudal solitary complex (cSC) are stimulated not only by hypercapnic acidosis, but by hyperoxia as well. While a cellular mechanism for the CO2response has yet to be isolated, previous data show that a redox-sensitive mechanism underlies neuronal excitability to hyperoxia. However, it remains unknown how changes in Po2affect the production of reactive oxygen and nitrogen species (RONS) in the cSC that can lead to increased cellular excitability and, with larger doses, to cellular dysfunction and death. To this end, we used fluorescence microscopy in real time to determine how normobaric hyperoxia increases the production of key RONS in the cSC. Because neurons in the region are CO2sensitive, we also examined the potential effects of CO2narcosis, used during euthanasia before brain slice harvesting, on RONS production. Our findings show that normobaric hyperoxia (0.4 → 0.95 atmospheres absolute O2) increases the fluorescence rates of fluorogenic dyes specific to both superoxide and nitric oxide. Interestingly, different results were seen for superoxide fluorescence when CO2narcosis was used during euthanasia, suggesting long-lasting changes in superoxide production and/or antioxidant activity subsequent to CO2narcosis before brain slicing. Further research needs to distinguish whether the increased levels of RONS reported here are merely increases in oxidative and nitrosative signaling or, alternatively, evidence of redox and nitrosative stress.

Two faces of nitric oxide: implications for cellular mechanisms of oxygen toxicity

2009 ◽  
Vol 106 (2) ◽  
pp. 662-667 ◽  
Author(s):  
Barry W. Allen ◽  
Ivan T. Demchenko ◽  
Claude A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Central Nervous System ◽  
Nervous System ◽  
Lung Injury ◽  
Nitrosative Stress ◽  
Organs At Risk ◽  
Chemical Species ◽  
Oxygen Toxicity ◽  
Spatial Effects ◽  
Cellular Mechanisms

Recent investigations have elucidated some of the diverse roles played by reactive oxygen and nitrogen species in events that lead to oxygen toxicity and defend against it. The focus of this review is on toxic and protective mechanisms in hyperoxia that have been investigated in our laboratories, with an emphasis on interactions of nitric oxide (NO) with other endogenous chemical species and with different physiological systems. It is now emerging from these studies that the anatomical localization of NO release, which depends, in part, on whether the oxygen exposure is normobaric or hyperbaric, strongly influences whether toxicity emerges and what form it takes, for example, acute lung injury, central nervous system excitation, or both. Spatial effects also contribute to differences in the susceptibility of different cells in organs at risk from hyperoxia, especially in the brain and lungs. As additional nodes are identified in this interactive network of toxic and protective responses, future advances may open up the possibility of novel pharmacological interventions to extend both the time and partial pressures of oxygen exposures that can be safely tolerated. The implications of a better understanding of the mechanisms by which NO contributes to central nervous system oxygen toxicity may include new insights into the pathogenesis of seizures of diverse etiologies. Likewise, improved knowledge of NO-based mechanisms of pulmonary oxygen toxicity may enhance our understanding of other types of lung injury associated with oxidative or nitrosative stress.

Ionic transport mechanisms underlying fluid secretion by the pancreas

1981 ◽  
Vol 296 (1080) ◽  
pp. 167-178 ◽  
Keyword(s):  
Carbonic Acid ◽  
Basolateral Membrane ◽  
Extracellular Fluid ◽  
Fluid Secretion ◽  
Bicarbonate Concentration ◽  
Cellular Mechanisms ◽  
Luminal Membrane ◽  
Sodium Gradient ◽  
Characteristic Features ◽  
Sodium And Potassium

The pancreas is a ‘leaky’ epithelium and secretes a juice in which sodium and potassium have concentrations similar to those of plasma. The characteristic features of the secretion are its isosmolality and its high bicarbonate concentration. It is the latter that has attracted considerable attention. Secretion in the isolated cat pancreas is directly proportional to the bicarbonate concentration in the nutrient fluid. The ability of the gland to secrete weak acids has led to the view that because of the very different chemical nature of the anions, it is most likely that it is a component common to all buffers, the proton, that is subject to active transport. This is supported by the decrease in pH and the increase in p co 2 of the venous effluent when secretion occurs and the sensitivity of secretion to the pH of the nutritional extracellular fluid. It is proposed that the cellular mechanisms are as follows: CO 2 diffuses into the cell and is hydrated to carbonic acid under the influence of carbonic anhydrase. The bicarbonate ion so formed diffuses into the ductular lumen and the proton is transported backwards through the epithelium with a proton pump (Mg 2+ -ATPase) provisionally located in the luminal membrane and a hydrogen-sodium exchange carrier located in the basolateral membrane. Energy for the latter process is derived from the sodium gradient between extracellular fluid and cell. This gradient is maintained by a (Na + +K + )-ATPase also located in the basolateral membrane. Chloride appears to be transported partly through a chloride-bicarbonate exchange mechanism, but largely passively together with a large sodium and potassium com ponent through the paracellular pathway. Osmotic equilibrium is likely to occur in the small ductules.

scholarly journals Characterization of the chemosensitive response of individual solitary complex neurons from adult rats

2009 ◽  
Vol 296 (3) ◽  
pp. R763-R773 ◽  
Author(s):  
Nicole L. Nichols ◽  
Daniel K. Mulkey ◽  
Katherine A. Wilkinson ◽  
Frank L. Powell ◽  
Jay B. Dean ◽  
...  
Keyword(s):  
Steady State ◽  
Firing Rate ◽  
Hypercapnic Acidosis ◽  
Neonatal Rats ◽  
Patch Clamp Technique ◽  
Adult Rats ◽  
Whole Cell Patch Clamp ◽  
Patch Pipette ◽  
Solitary Complex

We studied the CO2/H+-chemosensitive responses of individual solitary complex (SC) neurons from adult rats by simultaneously measuring the intracellular pH (pHi) and electrical responses to hypercapnic acidosis (HA). SC neurons were recorded using the blind whole cell patch-clamp technique and loading the soma with the pH-sensitive dye pyranine through the patch pipette. We found that SC neurons from adult rats have a lower steady-state pHi than SC neurons from neonatal rats. In the presence of chemical and electrical synaptic blockade, adult SC neurons have firing rate responses to HA (percentage of neurons activated or inhibited and the magnitude of response as determined by the chemosensitivity index) that are similar to SC neurons from neonatal rats. They also have a typical response to isohydric hypercapnia, including decreased ΔpHi, followed by pHi recovery, and increased firing rate. Thus, the chemosensitive response of SC neurons from adults is similar to the chemosensitive response of SC neurons from neonatal rats. Because our findings for adults are similar to previously reported values for neurons from neonatal rats, we conclude that intrinsic chemosensitivity is established early in development for SC neurons and is maintained throughout adulthood.

scholarly journals Acute hypercapnic hyperoxia stimulates reactive species production in the caudal solitary complex of rat brain slices but does not induce oxidative stress

2016 ◽  
Vol 311 (6) ◽  
pp. C1027-C1039 ◽  
Author(s):  
Geoffrey E. Ciarlone ◽  
Jay B. Dean
Keyword(s):  
Oxidative Stress ◽  
Rat Brain ◽  
Nitrosative Stress ◽  
Brain Slices ◽  
Radical Mechanism ◽  
Oxidative And Nitrosative Stress ◽  
Fenton Chemistry ◽  
Nitrated Lipids ◽  
Species Production ◽  
Solitary Complex

Central CO2 chemoreceptive neurons in the caudal solitary complex (cSC) are stimulated by hyperoxia via a free radical mechanism. Hyperoxia has been shown to increase superoxide and nitric oxide in the cSC, but it remains unknown how changes in Pco2 during hyperoxia affect the production of O2-dependent reactive oxygen and nitrogen species (RONS) downstream that can lead to increased levels of oxidative and nitrosative stress, cellular excitability, and, potentially, dysfunction. We used real-time fluorescence microscopy in rat brain slices to determine how hyperoxia and hypercapnic acidosis (HA) modulate one another in the production of key RONS, as well as colorimetric assays to measure levels of oxidized and nitrated lipids and proteins. We also examined the effects of CO2 narcosis and hypoxia before euthanasia and brain slice harvesting, as these neurons are CO2 sensitive and hypothesized to employ CO2/H+ mechanisms that exacerbate RONS production and potentially oxidative stress. Our findings show that hyperoxia ± HA increases the production of peroxynitrite and its derivatives, whereas increases in Fenton chemistry are most prominent during hyperoxia + HA. Using CO2 narcosis before euthanasia modulates cellular sensitivity to HA postmortem and enhances the magnitude of the peroxynitrite pathway, but blunts the activity of Fenton chemistry. Overall, hyperoxia and HA do not result in increased production of markers of oxidative and nitrosative stress as expected. We postulate this is due to antioxidant and proteosomal removal of damaged lipids and proteins to maintain cell viability and avoid death during protracted hyperoxia.

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